Carboxylic Acid Derivatives Display Potential Selectivity for Human Histone Deacetylase 6: Structure-Based Virtual Screening Molecular Docking and Dynamics Simulation Studies

dc.contributor.authorUba, Abdullahi Ibrahim
dc.contributor.authorYelekçi, Kemal
dc.date.accessioned2019-06-27T08:04:44Z
dc.date.available2019-06-27T08:04:44Z
dc.date.issued2018
dc.departmentFakülteler, Mühendislik ve Doğa Bilimleri Fakültesi, Biyoinformatik ve Genetik Bölümüen_US
dc.description.abstractHuman histone deacetylase 6 (HDAC6) has been shown to play a major role in oncogenic cell transformation via deacetylation of alpha-tubulin making it a viable target of anticancer drug design and development. The crystal structure of HDAC6 catalytic domain 2 has been recently made available providing avenues for structure-based drug design campaign. Here in our continuous effort to identify potentially selective HDAC6 inhibitors structure-based virtual screening of similar to 72 461 compounds was carried out using Autodock Vina. The top 100 compounds with calculated Delta G < -10 kcal/mol were manually inspected for binding mode orientation. Furthermore the top 20 compounds with reasonable binding modes were evaluated for selectivity by further docking against HDAC6 and HDAC7 using Autodock4. Four compounds with a carboxylic fragment displayed potential selectivity for HDAC6 over HDAC7 and were found to have good druglike and ADMET properties. Their docking complexes were then submitted to 10 ns-molecular dynamics (MD) simulation using nanoscale MD (NAMD) software to examine the stability of ligand binding modes. These predicted inhibitors remained bound to HDAC6 in the presence of water and ions and the root-mean-square deviation (RMSD) radius of gyration (Rg) and nonbond distance (protein-ligand) profiles suggested that they might be stable over time of the simulation. This study may provide scaffolds for further lead optimization towards the design of HDAC6 inhibitors with improved selectivity. (C) 2018 Elsevier Ltd. All rights reserved.en_US]
dc.identifier.citation18
dc.identifier.doi10.1016/j.compbiolchem.2018.05.004en_US
dc.identifier.endpage142
dc.identifier.issn1476-9271en_US
dc.identifier.issn1476-928Xen_US
dc.identifier.issn1476-9271
dc.identifier.issn1476-928X
dc.identifier.pmid29859380en_US
dc.identifier.scopus2-s2.0-85047621342en_US
dc.identifier.scopusqualityQ2
dc.identifier.startpage131en_US
dc.identifier.urihttps://hdl.handle.net/20.500.12469/981
dc.identifier.urihttps://doi.org/10.1016/j.compbiolchem.2018.05.004
dc.identifier.volume75en_US
dc.identifier.wosWOS:000437057500015en_US
dc.institutionauthorUba, Abdullahi Ibrahimen_US
dc.institutionauthorYelekçi, Kemal
dc.language.isoenen_US
dc.publisherElsevier Scienceen_US
dc.relation.journalComputational Biology and Chemistryen_US
dc.relation.publicationcategoryMakale - Uluslararası Hakemli Dergi - Kurum Öğretim Elemanıen_US
dc.rightsinfo:eu-repo/semantics/closedAccessen_US
dc.subjectStructure-based virtual screeningen_US
dc.subjectADMET predictionen_US
dc.subjectMolecular dockingen_US
dc.subjectMolecular dynamics simulationen_US
dc.subjectHDAC6-selective inhibitorsen_US
dc.subjectCarboxylic acid derivativesen_US
dc.titleCarboxylic Acid Derivatives Display Potential Selectivity for Human Histone Deacetylase 6: Structure-Based Virtual Screening Molecular Docking and Dynamics Simulation Studiesen_US
dc.typeArticleen_US
dspace.entity.typePublication
relation.isAuthorOfPublication9407938e-3d31-453b-9199-aaa8280a66c5
relation.isAuthorOfPublication.latestForDiscovery9407938e-3d31-453b-9199-aaa8280a66c5

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